Mitochondria‐targeted antioxidants Oyewole, Anne O.; Birch‐Machin, Mark A.
The FASEB journal,
December 2015, Letnik:
29, Številka:
12
Journal Article
Recenzirano
ABSTRACT
Redox homeostasis is maintained by the antioxidant defense system, which is responsible for eliminating a wide range of oxidants, including reactive oxygen species (ROS), lipid peroxides, ...and metals. Mitochondria‐localized antioxidants are widely studied because the mitochondria, the major producers of intracellular ROS, have been linked to the cause of aging and other chronic diseases. Mitochondria‐targeted antioxidants have shown great potential because they cross the mitochondrial phospholipid bilayer and eliminate ROS at the heart of the source. Growing evidence has identified mitochondria‐targeted antioxidants, such as MitoQ and tiron, as potentially effective antioxidant therapies against the damage caused by enhanced ROS generation. This literature review summarizes the current knowledge on mitochondria‐targeted antioxidants and their contribution to the body's antioxidant defense system. In addition to addressing the concerns surrounding current antioxidant strategies, including difficulties in targeting antioxidant treatment to sites of pathologic oxidative damage, we discuss promising therapeutic agents and new strategic approaches.—Oyewole, A. O., BirchMachin, M. A. Mitochondria‐targeted antioxidants. FASEB J. 29, 4766–4771 (2015). www.fasebj.org
The ability of solar ultraviolet (UV) to induce skin cancer and photoaging is well recognized. The effect of the infrared (IR) and visible light (Vis) components of solar radiation on skin and their ...interaction with UV is less well known. This study compared the effects of physiologically relevant doses of complete (UV + Vis + IR) solar‐simulated light and its individual components on matched primary dermal fibroblasts and epidermal keratinocytes from human donors on three biomarkers of cellular damage (reactive oxygen species (ROS) generation, mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) damage). There was a greater induction of ROS, mtDNA, and nDNA damage with the inclusion of the visible and IR components of solar‐simulated light in primary fibroblast cells compared to primary keratinocytes (P < .001). Experiments using exposure to specific components of solar light alone or in combination showed that the UV, Vis, and IR components of solar light synergistically increased ROS generation in primary fibroblasts but not primary keratinocytes (P < .001). Skin cell lines were used to confirm these findings. These observations have important implications for different skin cell type responses to the individual and interacting components of solar light and therefore photodamage mechanisms and photoprotection interventions.
The mitochondrial theory of aging remains one of the most widely accepted aging theories and implicates mitochondrial electron transport chain dysfunction with subsequent increasing free radical ...generation. Recently, complex II of the electron transport chain appears to be more important than previously thought in this process, suggested predominantly by nonhuman studies. We investigated the relationship between complex II and aging using human skin as a model tissue. The rate of complex II activity per unit of mitochondria was determined in fibroblasts and keratinocytes cultured from skin covering a wide age range. Complex II activity significantly decreased with age in fibroblasts (P = 0.015) but not in keratinocytes. This was associated with a significant decline in transcript expression (P = 0.008 and P = 0.001) and protein levels (P = 0.0006 and P = 0.005) of the succinate dehydrogenase complex subunit A and subunit B catalytic subunits of complex II, respectively. In addition, there was a significant decrease in complex II activity with age (P = 0.029) that was specific to senescent skin cells. There was no decrease in complex IV activity with increasing age, suggesting possible locality to complex II.
Alterations in metabolism in skin are accelerated by environmental stressors such as solar radiation, leading to premature aging. The impact of aging on mitochondria is of interest given their ...critical role for metabolic output and the finding that environmental stressors cause lowered energy output, particularly in fibroblasts where damage accumulates. To better understand these metabolic changes with aging, we performed an in‐depth profiling of the expression patterns of dermal genes in face, forearm, and buttock biopsies from females of 20–70 years of age that encode for all subunits comprising complexes I‐V of the mitochondrial electron transport chain. This complements previous preliminary analyses of these changes. “Oxidative phosphorylation” was the top canonical pathway associated with aging in the face, and genes encoding for numerous subunits had decreased expression patterns with age. Investigations on fibroblasts from older aged donors also showed decreased gene expression of numerous subunits from complexes I‐V, oxidative phosphorylation rates, spare respiratory capacity, and mitochondrial number and membrane potential compared to younger cells. Treatment of older fibroblasts with nicotinamide (Nam) restored these measures to younger cell levels. Nam increased complexes I, IV, and V activity and gene expression of representative subunits. Elevated mt‐Keima staining suggests a possible mechanism of action for these restorative effects via mitophagy. Nam also improved mitochondrial number and membrane potential in younger fibroblasts. These findings show there are significant changes in mitochondrial functionality with aging and that Nam treatment can restore bioenergetic efficiency and capacity in older fibroblasts with an amplifying effect in younger cells.
A decline in mitochondrial quality was observed in primary human skin fibroblasts with age, with a decrease in mitochondrial complex gene expression, oxidative phosphorylation rates, spare respiratory capacity, mitochondrial number, membrane potential, and mitophagy. The addition of Nam (nicotinamide, vitamin B3) improved these age‐related changes in cells from older aged individuals to levels observed in younger individuals, with an amplifying effect seen in younger cells.
Skin ageing is a complex process involving both internal and external factors, which leads to a progressive loss of cutaneous function and structure. Solar radiation is the primary environmental ...factor implicated in the development of skin ageing, and the term photoaging describes the distinct clinical, histological and structural features of chronically sun‐exposed skin. The changes that accompany photoaging are undesirable for aesthetic reasons and can compromise the skin and make it more susceptible to a number of dermatological disorders. As a result, skin ageing is a topic that is of growing interest and concern to the general population, illustrated by the increased demand for effective interventions that can prevent or ameliorate the clinical changes associated with aged skin. In this viewpoint essay, we explore the role that mitochondria play in the process of skin photoaging. There is continuing evidence supporting the proposal that mitochondrial dysfunction and oxidative stress are important contributing factors in the development of skin photoaging. Further skin‐directed mitochondrial research is warranted to fully understand the impact of mitochondrial status and function in skin health. A greater understanding of the ageing process and the regulatory mechanisms involved could lead to the development of novel preventative interventions for skin ageing.
Aging is an inherently stochastic process, and its hallmark is heterogeneity between organisms, cell types, and clonal populations, even in identical environments. The replicative lifespan of primary ...human cells is telomere dependent; however, its heterogeneity is not understood. We show that mitochondrial superoxide production increases with replicative age in human fibroblasts despite an adaptive UCP-2-dependent mitochondrial uncoupling. This mitochondrial dysfunction is accompanied by compromised Ca(2+)i homeostasis and other indicators of a retrograde response in senescent cells. Replicative senescence of human fibroblasts is delayed by mild mitochondrial uncoupling. Uncoupling reduces mitochondrial superoxide generation, slows down telomere shortening, and delays formation of telomeric gamma-H2A.X foci. This indicates mitochondrial production of reactive oxygen species (ROS) as one of the causes of replicative senescence. By sorting early senescent (SES) cells from young proliferating fibroblast cultures, we show that SES cells have higher ROS levels, dysfunctional mitochondria, shorter telomeres, and telomeric gamma-H2A.X foci. We propose that mitochondrial ROS is a major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan.
Tissue engineering and cell therapy for regenerative medicine have great potential to treat chronic disorders. In musculoskeletal disorders, mesenchymal stromal cells (MSCs) have been identified as a ...relevant cell type in cell and regenerative strategies due to their multi-lineage potential, although this is likely to be a result of their trophic and immunomodulatory effects on other cells. This PRISMA systematic review aims to assess whether the age of the patient influences the chondrogenic potential of MSCs in regenerative therapy. We identified a total of 3027 studies after performing a search of four databases, including Cochrane, Web of Science, Medline, and PubMed. After applying inclusion and exclusion criteria, a total of 14 papers were identified that were reviewed, assessed, and reported. Cell surface characterization and proliferation, as well as the osteogenic, adipogenic, and chondrogenic differentiation, were investigated as part of the analysis of these studies. Most included studies suggest a clear link between aged donor MSCs and diminished clonogenic and proliferative potential. Our study reveals a heterogeneous and conflicting range of outcomes concerning the chondrogenic, osteogenic, and adipogenic potential of MSCs in relation to age. Further investigations on the in vitro effects of chronological age on the chondrogenic potential of MSCs should follow the outcomes of this systematic review, shedding more light on this complex relationship.
With a large proportion of the world's population living in areas where air quality does not meet current WHO guidelines, combined with the knowledge that pollutants can interact with human skin, it ...is now of even greater importance that the effects of air pollutant exposure on human skin be investigated. To evaluate the damaging effects of a known component of air pollution (particulate matter) on human primary dermal fibroblasts. These studies were undertaken by exposing primary human dermal fibroblasts to different concentrations of particulate matter and analyzing the effects over time using resazurin reduction assays. Immunofluorescence microscopy was used to determine if particulate matter caused activation of the aryl hydrocarbon receptor, and phosphorylation of histone H2AX, a known marker of double‐strand DNA breaks. Dot blotting was also used to analyze expression changes in secreted MMP‐1, MMP‐3, and TGFβ. Particulate matter was found to dose‐dependently increase cellular viability, activate the aryl hydrocarbon receptor, increase double‐strand DNA breaks, and increase the expression of MMP‐1, MMP‐3, and TGFβ. With the potential of air pollutants such as particulate matter to not only modulate the expression of proteins implicated in skin aging, but also affect cells at a genetic level, brings a pressing need for further investigation so protective strategies can be implemented.
Bad air gets under your skin Koohgoli, Roxanna; Hudson, Laura; Naidoo, Khimara ...
Experimental dermatology,
20/May , Letnik:
26, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Air pollution is increasing beyond previous estimates and is viewed as the world's largest environmental health risk factor. Numerous clinical and epidemiological studies have highlighted the adverse ...effects of environmental pollutants on health. Although there is comparatively less research investigating the cutaneous effects of ambient pollution, there is growing recognition of the adverse effects on skin. In this article, we provide an overview of the nature of environmental pollution and highlight the current evidence detailing the effects on cutaneous health. There is convincing evidence demonstrating that air pollution has a detrimental impact on skin and can exacerbate skin disease. Further epidemiological and experimental studies are required to assess the short‐ and long‐term deleterious effects of ambient pollutant exposure on skin. The future challenge would be to use this evidence to develop specific strategies to protect against pollution‐induced damage and prevent the effects of “bad air getting under our skin.”
Bone cell interaction with extracellular matrix (ECM) microenvironment is of critical importance when engineering surface interfaces for bone regeneration. In this work layer-by-layer films of type I ...collagen (coll), the major constituent of bone ECM, and heparin (hep), a glycosaminoglycan, were assembled on poly(l-lactic acid) (PLLA) substrates to evaluate the impact of the biomacromolecular coating on cell activity. The surface modification of PLLA demonstrated that the hep/coll multilayer is stable after 10 bilayers (confirmed by contact angle, infrared spectroscopy, and morphological analysis). This simple approach provided novel information on the effect of heparin on type I collagen hierarchical organization and subsequent cell response of osteoblast-like (MC3T3-E1) and human bone marrow-derived mesenchymal stem cells (hMSCs). Interestingly, the number of deposited heparin layers (1 or 10) appeared to play an important role in the self-assembly of collagen into fibrils, stabilizing the fibrous collagen layer, and potentially impacting hMSCs activity.
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